New research highlights the potential benefits and detriments of treatment strategies for ADHD, which include both pharmacological and nonpharmacological options (Table).
Is psychosis a concern?
Stimulants are the first line of treatment for ADHD and are typically well tolerated. Although there are potential adverse effects associated with stimulant administration, the most common are usually transient or dose related. One of the more serious effects is stimulant-induced psychosis.
To explore this risk, Moran and colleagues1 examined the records of 337,919 young persons aged 13 to 25 who had an ADHD diagnosis and were newly prescribed a stimulant medication. The researchers found 343 episodes of new-onset psychosis among the 221,846 study-matched population over an 11-year period. The median time from which the first stimulant was dispensed to the psychotic episode was 128 days.
The researchers concluded that the risk of new-onset psychosis was approximately doubled for individuals who received amphetamine compared with those who received methylphenidate. This supported their hypothesis, which was based on the similarities between idiopathic psychosis and the biologic effects of amphetamine. Individuals with primary psychosis have higher presynaptic dopaminergic capacity, which is an index of dopamine release.
Limitations of the study included: unmeasured confounding factors (ie, underreporting of substance use disorder), not knowing if the patients actually took the stimulant medication (there is a high rate of diversion, which is greater for amphetamine than methylphenidate), and the study findings, are not generalizable as the data were only from commercial insurance claims and did not take into account patients with no insurance or public insurance.
While the exact therapeutic mechanism of action of stimulants is unknown, they are thought to increase the availability of dopamine in the postsynaptic cleft by blocking the reuptake of dopamine. Amphetamine blocks the ability of the dopamine transporter to remove dopamine from the synapse, facilitates the reuptake of dopamine across the cell membrane, increases the release of vesicular dopamine (accumulates in the cytoplasm), and inhibits the degradative enzymes monoamine oxidase A and B. Methylphenidate binds to the dopamine transporter in the presynaptic cell membrane, blocking the reuptake of dopamine and, therefore, causing an increase in extracellular dopamine. The difference is that methylphenidate does not promote dopamine release from synaptic vesicles. Moreover, amphetamine induces the release of four times as much dopamine as methylphenidate.2 This increase of dopamine may contribute to adverse effects such as stimulant-induced psychosis.
Dr Griffin is Assistant Professor of Psychiatry, the Medical Director of Outpatient Child and Adolescent Psychiatry, and the Director of the Child and Adolescent ADHD Clinic at Rush University Medical Center, Chicago, IL. Dr Harari is a first-year Child and Adolescent Psychiatry Fellow at Rush University Medical Center. The authors report no conflicts of interest concerning the subject matter of this article.
1. Moran LV, Ongur D, Hsu J, et al. Psychosis with methylphenidate or amphetamine in patients with ADHD. N Engl J Med. 2019;380:1128-1138.
2. Schiffer WK, Volkow ND, Fowler JS, et al. Therapeutic doses of amphetamine or methylphenidate differentially increase synaptic and extracellular dopamine. Synapse. 2006;59:243-51.
3. Young D, Scoville WB. Paranoid psychosis in narcolepsy and the possible danger of Benzedrine. Med Clin North Am. 1938;22:637-646.
4. Ney PG. Psychosis in a child, associated with amphetamine administration. Can Med Assoc J. 1967;97:1026-1029.
5. Lucas AR, Weiss M. Methylphenidate hallucinosis. JAMA. 1971;217:1079-1081.
6. dosReis S, Park A, Ng X, et al. Caregiver treatment preferences for children with a new versus existing attention-deficit/hyperactivity. J Child Adolesc Psychopharmacol. 2017;27:234-242.
7. Barbaresi WJ, Colligan RC, Weaver AL, et al. Mortality, ADHD, and psychosocial adversity in adults with childhood ADHD: a prospective study. Pediatrics. 2013;131:637-644.
8. Danielson ML, Bitsko RH, Ghandour RM et al. Prevalence of parent-reported ADHD diagnosis and associated treatment among U.S. children and adolescents. J Child Adolesc Psychol. 2016;47:199-212.
9. McGough JJ, Sturm A, Cowen J, et al. Double-blind, sham-controlled, pilot study of trigeminal nerve stimulation for attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2019;58:403-411.
10. McGough JJ, Loo SK, Sturm A et al. An eight-week, open-trial, pilot feasibility study of trigeminal nerve stimulation in youth with attention-deficit/hyperactivity disorder. Brain Stimul. 2015;8:299-304.